The overall goal of this program is to advance our understanding of the physiology of insulin secretion and its role in diabetes. The program has made significant contributions to understanding beta-cell function in diabetes over more than 20 years of continuous funding. We plan to continue to define the effects of diabetes-susceptibility genes on beta-cell function in humans and to study the mechanisms responsible for beta-cell dysfunction in animal models of diabetes. We will define the effects of specific diabetes-susceptibility genes on insulin secretion and insulin action in human subjects at high risk for the development of type 2 diabetes. Complementary studies in animal models and cultured cells will investigate the roles of replication, apoptosis and reduced a-cell mass in the pathogenesis of abnormal beta-cell function associated with certain diabetes-susceptibility genes. There are three specific aims: Specific Aim 1;To study the effects on insulin secretion of genes that affect risk for type 2 diabetes in humans. We will test the hypothesis that genetic variants that affect risk for diabetes are associated with measurable effects on insulin secretion and specifically on p-cell adaptation to insulin resistance. We postulate that genetic variation in the genes for Kir6.2 (KCNJ11) and calpain-10 (CAPN10) that increases risk for diabetes will be associated with impaired a-cell adaptation to insulin resistance while the ability to adapt to insulin resistance will be retained with variation in the gene for PPARgamma2 that protects against type 2 diabetes. Specific Aim 2: To study the role of the calpain system of cysteine proteases in the regulation of beta-cell apoptosis and mass. We will test the hypothesis that calpain 10 and other calpains play an important role in the regulation of a-cell apoptosis and beta-cell mass and regulate these processes in vivo. Specific Aim 3: To study the role of transcription factors associated with maturity onset diabetes of the young (MODY) in the regulation of a-cell apoptosis and mass. We will test the hypothesis that a decrease in a-cell mass resulting from an increase in apoptosis is an important mechanism responsible for beta-cell dysfunction and diabetes in subjects with MODY.